Preparation of dl-endo-Fenchyl Alcohol. The reduction of fenchone was carried out on a preparative scale to test the utility of the procedure for such preparations. In a 1-1. flask was placed 750 ml. of distilled tetrahydrofuran, and 0.4 mole of lithium aluminum hydride was added. The mixture was stirred overnight with a magnetic stirrer. The solids were allowed to settle and an aliquot of the clear solution was analyzed for dissolved hydride by the usual procedure. A sufficient quantity of the clear solution was placed in a 1-l., three-neck flask, fitted with condenser, stirrer, and addition funnel, to provide 0.3 mole of the reagent. The solution was cooled to 0" and 0.9 mole of methanol was slowly added (exothermic reaction) as the hydrogen evolved was vented. Then 35 g. (0.25 mole) of dl-fenchone was added from the dropping funnel at such a rate that the temperature
could be maintained at approximately 0". After addition was complete, the solution was stirred at 0" for 1 hr. Residual hydride was then destroyed by the slow addition of water. The reaction mixture was then transferred to a separatory funnel, ether was added, and then the mixture was treated with a saturated solution of sodium potassium tartrate. The organic phase was separated, the aqueous layer was extracted with ether, and the combined ether extract was dried over anhydrous magnesium sulfate. The solvents were removed on a rotary evaporator. Distillation provided 30.7 g., 80 % yield, of dl-endo-fenchyl alcohol, b.p. 4345 O (1 mm.), 97 % isomerically pure by gas chromatographic examination, m.p. p-nitrobenzoate 93-94.5 " (lit.26m.p. 94-95 "). (26) G. Komppa and S . Beckmann, Ber., 68, 10 (1935).
Intramolecular Catalysis of Ketone Enolization in o-Acylbenzoic Acids' Edwin T. Harper2 and Myron L. Bender
Contributionf r o m the Department of Chemistry, Northwestern University, Evanston, Illinois. Received June 8,1965 The kinetics of enolization of o-isobutyrylbenzoic acid has been measured in aqueous solution f r o m p H 0 to I 1 ut 25". Enolization rates were calculated f r o m spectrophotometrically datermined rates of iodination. Four kinetic terms contributed to the enolization: ( 1 ) the reaction of hydronium ion and the undissociated carboxylic acid; ( 2 ) the reaction of hydroxide ion and the carboxylate ion; ( 3 ) the reaction of the undissociated carboxylic acid; and (4)the reaction of the carboxylate anion. Of these four reactions, the last is the most important, being the predominant reaction from p H 2.5 to 10. In this region, the rate of the enolization reaction is dependent on the ionization of a group of p K , = 4.4 and is unaffected by external buffers. The facile catalysis of enolization in the carboxylate anion can be mechanistically interpreted in terms of intramolecular general basic catalysis by the o-carboxylate ion, or alternatively in terms of intramolecular general acidic catalysis by the o-carboxylic acid group in a reaction with hydroxide ion. The former interpretation is preferred on kinetic and steric grounds. Intramolecular catalysis by o-carboxylate ion corresponds in eficiency to a concentration of the corresponding intermolecular catalyst of the order of 50 M . This intramolecular catalysis of enolization may serve as a model f o r the intracomplex catalysis of enolization of dihydroxyacetone phosphate by the enzyme aldolase. Introduction The initiating step of many organic reactions, synthetic and biochemical, is the transfer of a hydrogen (1) This investigation was supported by a grant from the National Science Foundation. (2) National Institutes of Health Postdoctoral Research Fellow, 1962-1964.
atom from a carbonyl compound to a base, leading to the formation of an enolate ion or enol. Catalysis of enolization has been one of the most thoroughly studied of all organic catalytic p r o c e s ~ e s . ~Recent ,~ work has attempted to extend our understanding to enzymecatalyzed reactions which depend on enoli~ation."~ If an enzymatic group of an enzyme-substrate complex catalyzes the enolization of the substrate, the process may be described as an intracomplex catalysis. A suitable model for the elucidation of possible mechanisms of intracomplex catalysis has been the use of intramolecular catalysis.* Therefore, it seemed desirable to examine the intramolecular catalysis of enolization. In classic work on the mechanism of enolization, Ingold, Wilson, and Hsug compared the rates of racemization and bromination of 2 (0-carboxybenzy1)indanone, in which intramolecular catalysis of enolization by the carboxyl group could occur, but they did not discuss this possibility. The enolization of a number of aliphatic ketones containing potential intramolecular catalytic groups has been investigated. Both the bromination of levulinic acidlo and the (3) R. P. Bell, "Acid-Base Catalysis," Oxford University Press, London, 1941. (4) R. P. Bell, "The Proton in Chemistry," Cornell University Press, Ithaca, N. Y.,1959, pp. 140-172. (5) B. L. Horecker, Federation Proc., 21, 1023 (1962). (6) 0. C. Richards and W. J. Rutter, J. Biol. Chem., 236, 3185 (1961); A. H. Mehler, ibid., 238, 100 (1963). (7) C. D. Gutsche, R. S . Buriks, K. Nowotny, and H. Grassner, J . Am. Chem. SOC.,84, 3775 (1962). (8) M. L. Bender, Chem. Rev., 60, 56 (1960); T. C. Bruice, Brookhaven Symp. Biol., 15, 52 (1962). (9) C. I
